DNA Mismatch Repair Protein Immunohistochemistry and MLH1 Promotor Methylation Testing for Practical Molecular Classification and the Prediction of Prognosis in Endometrial Cancer.

Jisup Kim,Hanbyoul Cho,Doo Byung Chay,Seong Jin Cho,Jin Kyoung Kong,Bang Hyun Lee,Wookyeom Yang,Jae-Hoon Kim,Soonwon Hong

doi:10.3390/cancers10090279

Abstract

The incidence of endometrial cancer is rapidly increasing worldwide, and its molecular classification has gained importance for new therapeutic approaches. This study sought to examine the clinicopathologic features and immune markers associated with the DNA mismatch repair (MMR) status and MLH1 promoter methylation status of endometrial cancer patients. A total of 173 patients with primary endometrial cancer who had received a hysterectomy were evaluated for four MMR proteins (MLH1, MSH2, MSH6, and PMS2), immune markers (CD8, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1)) and p53 by immunohistochemistry (IHC), followed by an MLH1 methylation test. Patients were classified into MMR deficiency or proficiency, sporadic cancer, or probable Lynch syndrome (PLS), and the clinicopathologic features (including the expression of peritumoral immune markers) and prognosis of each group were compared. Patients with MMR deficiency or PLS showed an increase in immune markers compared those with MMR proficiency or sporadic cancer, respectively, and PLS demonstrated higher immune marker expression than MLH1 promoter methylation. Regarding prognosis, patients with MMR deficiency showed significant adverse overall survival (OS) when in stages I and II. Practical molecular classifications based on p53 staining results, in addition to MMR or PLS status, revealed an increased predictive ability for OS compared with the European Society of Medical Oncologists (ESMO) risk groups. The results of this study suggest that PLS may be a better candidate for an immune checkpoint inhibitor than MMR deficiency. The practical molecular classification contributes not only to the screening of Lynch syndrome, but also assists in predicting the prognosis in endometrial cancer.

Highlights

Introduction2–5% of endometrial cancer cases are presumed to be caused by genetic factors, of which Lynch syndrome is the most common [3]
Endometrial cancer is the most common gynecologic malignancy in the developed world; its incidence is rapidly increasing, and carries the highest disease burden [1,2].Approximately 2–5% of endometrial cancer cases are presumed to be caused by genetic factors, of which Lynch syndrome is the most common [3]
In the IHC analysis and MLH1 methylation test for the primary endometrioid carcinoma from 173 patients, loss of mismatch repair (MMR) IHC was observed in 45 cases (26.0%)

Summary

Introduction

2–5% of endometrial cancer cases are presumed to be caused by genetic factors, of which Lynch syndrome is the most common [3]. Endometrial cancer has been traditionally classified into two major subtypes: estrogen-related type I cancer, which is predominantly of an endometrioid histotype with favorable prognosis; and estrogen-unrelated type II cancer, which is a predominantly non-endometrioid histotype with unfavorable prognosis [6]. This classification has been challenged due to the clinicopathologic, biologic, and genetic heterogeneity of tumors, as well as for its inability to guide treatment modality [7]. More cost-effective and practical classification has been developed based on TCGA data by the ProMisE/Vancouver group [9] and the Leiden/TransPORTEC group [9,10]

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Discussion

Conclusion